title: Differences in 53BP1 and BRCA1 regulation between cycling and non-cycling cells.
abstract: BRCA1 and 53BP1 play decisive roles in the choice of DNA double-strand break repair mechanisms. BRCA1 promotes DNA end resection and homologous recombination (HR) during S/G 2 phases of the cell cycle, while 53BP1 inhibits end resection and facilitates non-homologous end-joining (NHEJ), primarily during G 1. This competitive relationship is critical for genome integrity during cell division. However, their relationship in the many cells in our body that are not cycling is unknown. We discovered profound differences in 53BP1 and BRCA1 regulation between cycling and non-cycling cells. Cellular growth arrest results in transcriptional downregulation of BRCA1 and activation of cathepsin-L (CTSL)-mediated degradation of 53BP1. Accordingly, growth-arrested cells do not form BRCA1 or 53BP1 ionizing radiation-induced foci (IRIF). Interestingly, cell cycle re-entry reverts this scenario, with upregulation of BRCA1, downregulation of CTSL, stabilization of 53BP1, and 53BP1 IRIF formation throughout the cycle, indicating that BRCA1 and 53BP1 are important in replicating cells and dispensable in non-cycling cells. We show that CTSL-mediated degradation of 53BP1, previously associated with aggressive breast cancers, is an endogenous mechanism of non-cycling cells to balance NHEJ (53BP1) and HR (BRCA1). Breast cancer cells exploit this mechanism to ensure genome stability and viability, providing an opportunity for targeted therapy.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology; St Louis University School of Medicine; St. Louis, MO USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Croke
authors.forename: Martin A
authors.initials: MA
authors.lastname: Neumann
authors.forename: David A
authors.initials: DA
authors.lastname: Grotsky
authors.forename: Ray
authors.initials: R
authors.lastname: Kreienkamp
authors.forename: Sree C
authors.initials: SC
authors.lastname: Yaddanapudi
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair; D004261:DNA Replication / Q000187:drug effects; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D061986:MCF-7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D056668:Cathepsin L; D007930:Leucine; C024974:E 64; D006918:Hydroxyurea
keywords: 53BP1; BRCA1; DNA repair; cathepsin L; cell cycle